The present invention relates to compounds and their compositions to be used in the hypertension therapy and prophylaxis. More specifically it relates to the use of said hypertensives for systemic and local use, in particular for the cardiovascular area. More specifically the present invention relates to new antihypertensive compounds having an improved performance.
The known compounds of the prior art used in the hypertension treatment generally have a limited efficacy. The hypertension treatment is usually carried out by administering to the patient the antihypertensives in association with other medicines active on the vascular system, such as for instance calcium-antagonists, diuretics, beta-blockers, ACE inhibitors. For example the antihypertensive antagonists of the angiotensin (ex. Losartan), the calcium antagonists (ex. dihydropyridines), diuretics (for example thiazidic derivatives, direct and undirect vasodilators (ex. Minoxidil, Zaprinast) are not able when used alone to assure the therapy success.
It is necessary moreover to point out that some antihypertensives cause side effects for the respiratory apparatus, such as bronchoconstriction, dyspnea. For instance the antihypertensive used in the angina pectoris and cardiac arrhythmias treatment, for instance Timolol and Propanolol, give said side effects.
Other antihypertensives induce vasodilatation through phosphodiesterases inhibition and show side effects for various apparatuses (gastrointestinal, cardiovascular, ocular, etc.) See for instance Sildenafil and Zaprinast.
The need was felt to have available compositions active in the hypertension pathology treatment for systemic and local use, in particular of the cardiovascular area, with improved therapeutic profile. In particular the need was felt, moreover, to have available antihypertensive medicines having a beta-blocking or antiphosphodiesterasic action with lower side effects.
The Applicant has unexpectedly and surprisingly found compounds and pharmaceutical compositions usable in the treatment of the hypertension pathologies for systemic and local use, particularly of the cardiovascular area, with improved therapeutic profile, and without the side effects of the known hypertensive medicines.
It is an object of the present invention nitrate salts of compounds having an antihypertensive activity, or pharmaceutical compositions thereof, for systemic and local use, particularly to be used for the cardiovascular area, said compounds being characterized in that they contain least a reactive group capable to be salified, said compounds being selected from the following classes:
Class (A1b): 
RA1=xe2x80x94O with RIIIA1 free valence, so as to form in combination with the carbon atom in 5 position a ketone group, RA1 together with RIA1 and the carbon atoms in 4 and 5 position of the heterocyclic ring in the compound of formula (A1b), with RIVA1 and RIIIA1 free valences, forms the aromatic ring having 6 carbon atoms containing a xe2x80x94COOH group: 
RIA1=H, Cl;
RIA1 with RA1, RIVA1, RIIIA1 and the carbon atoms in 4 and 5 position of the heterocyclic ring of formula (A1b) forms the aromatic ring containing a COOH group (IXc), RIA1 with RIVA1 and with the carbon atom in 4 position of the heterocyclic ring of formula (A1b) forms the following saturated ring having five carbon atoms: 
RIIA1=xe2x80x94(CH2)3xe2x80x94CH3, xe2x80x94Oxe2x80x94CH2xe2x80x94CH3;
RIIIA1=H, free valence,
RIIIA1 free valence with RIVA1 free valence forms a double bond between the carbon atoms in 4 and 5 position in the heterocyclic ring of formula (A1b),
RIIIA1 with RIVA1, RIVA1 and the carbon atoms in 4 and 5 position of the heterocyclic ring of formula (A1b) forms the aromatic ring containing a xe2x80x94COOH group (IXc);
RIVA1=free valence, RIVA1 along with RIA1 with the carbon atom in 4 position of the heterocyclic ring of formula (A1b) forms the saturated ring having five carbon atoms (IXd)
RIVA1 with RIIIA1, RIA1 and the carbon atoms in 4 and 5 position of the heterocyclic ring of formula (A1b) forms the aromatic ring containing a xe2x80x94COOH group (IXc),
RIVA1 with RIIIA1 both free valences form a double bond between the carbon atoms in 4 and 5 position of the heterocyclic ring of formula (A1b); 
known as Valsartan;
Class (A2):
the precursors of this class are the following ones: 1 (2H)-phthalazinone hydrazone (Hydralazine); 6-(1-piperidiny-1)-2,4-pyrimidinediamine 3-oxide (Minoxidil); 1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazol [4,3-d]pyrimidin-5-yl)-4-etoxyphenyl]sulphonyll-4-methyl-piperazine (Sildenafil), 2-(2-propyloxyphenyl)-8-azapurin-6-one (Zaprinast);
Class (A3): 
RIB1 and RIIB1, equal to or different from each other, are H, CH3, 
In the formula (XId) t=0, 1.
In the formula (XIe) YBB1 can have the following meanings: 
in the formula (XIf) Z=H, xe2x80x94OCH3;
in the formula (A3):
XIB1=xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94;
n and m, equal to or different from each other, are 0, 1; 
in the formula (XIp):
S1=H, CN, OCH3, CH3, xe2x80x94CH2xe2x80x94CH3, xe2x80x94Oxe2x80x94CH2xe2x80x94CONHxe2x80x94CH3, xe2x80x94COCH3, xe2x80x94COxe2x80x94(CH2)2xe2x80x94CH3, xe2x80x94Oxe2x80x94CH2xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, cyclopentyl, or 
S2=H, CH3, Cl, xe2x80x94SOCH3, xe2x80x94CONH2;
S1 with S2 and the carbon atoms in 2 and 3 position of the C6 aromatic ring of the same radical (XIp) forms the following ring: 
wherein:
[(*) atom adjacent to the aromatic ring of the formula XIpVII]
B=xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, (*)xe2x80x94COxe2x80x94CH2xe2x80x94;
A=xe2x80x94Oxe2x80x94, (*)xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94, (*)xe2x80x94Oxe2x80x94CH2xe2x80x94, (*)xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94,
A is a tertiary carbon atom and contemporaneously W1 is free valence so as to form a double bond xe2x80x94CHxe2x95x90CHxe2x80x94 between A and the carbon atom in 1xe2x80x2 position,
A in the ring having 5 atoms (XIpVII) is a tertiary carbon atom containing a substituent such that with the carbon atom in 1xe2x80x2 position and with one of the two W1 or W2 radicals, the other radical being free valence, forms an aromatic ring having 6 carbon atoms according to the following formula: 
W1=H, free valence, when W1 is free valence and A is a tertiary carbon atom as above defined, a double bond between A and the carbon atom in 1xe2x80x2 position is formed,
W1 together with W2, the carbon atom in 1xe2x80x2 position and the substituent A forms an aromatic ring having 6 carbon atoms;
W2=free valence, H, OH, xe2x80x94CH3, xe2x80x94ONO2, xe2x80x94O which with W1=free valence and the carbon atom in 1xe2x80x2 position forms a ketone group,
W2 together with W1, the carbon atom in 1xe2x80x2 position and the substituent A forms an aromatic ring having 6 carbon atoms; S3=H, F, Cl, OH, NO2,xe2x80x94CH2xe2x80x94COxe2x80x94NH2xe2x80x94(CH2)2xe2x80x94OCH3, xe2x80x94NHxe2x80x94COCH3, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH(CH3)2, xe2x80x94CH2xe2x80x94CH2xe2x80x94COOCH3, xe2x80x94NHxe2x80x94COxe2x80x94N(C2H5)2, xe2x80x94NHxe2x80x94COxe2x80x94(CH2)2xe2x80x94CH3, xe2x80x94NHxe2x80x94SO2xe2x80x94CH3xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94[cyclohexyl], xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94[cyclopropyl];
S4=H, Cl, xe2x80x94CH2xe2x80x94CH2xe2x80x94 which with the carbon atoms in 1 and 6 position of the aromatic ring of the same radical (XIp) and with XB1 in the formula (A3) equal to oxygen, being contemporaneously m n=1 and RVIIB1 free valence, forms the following ring: 
S4 is a tertiary carbon atom which with the carbon atoms in 1 and 6 position of the aromatic ring of the radical (XIp), and with the following components of the formula (A3): the carbon atom xe2x80x94|C|nxe2x80x94(n=1), the radical XB1 equal to oxygen (m=1), and RVIIB1 with RV1B1 free valences, forms the following ring: 
RVIB1=H, free valence;
RVIIB1=H, free valence;
Other compounds belonging to this class are the following: 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl] benzamide (Labetalol), 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl] piperazine (Terazosin), 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl) piperazine (Prazosin);
Class (A4):
the following groups of compounds belong to this class:
(A4a):
xcex2-[(2-methylpropoxy) methyl]-N-phenyl-N-(phenylmethyl)-1-pyrrolidineethanamine (Bepridil), (2S-cis)-3-(acetyloxy)-8-chloro-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one (Clentiazem), (2S-cis)-3-(acetyloxy)-5-[2-(dimethylamino) ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one (Diltiazem), xcex3-phenyl-N-(1-phenylethyl)benzene-propanamine (Fendiline), xcex1[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino] propyl]-3,4,5-trimethoxy-xcex1-(1-methylethyl)-benzeneacetonitrile (Gallopamil), (1S-cis) methoxyacetic acid 2-[2[[3-(1H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-naphthalenyl ester (Mibefradil), N-(1-methyl-2-phenylethyl)-xcex3-phenylbenzenepropanamine (Prenylamine), (R)-2-[2-[3-[[2-(1,3-bezodioxol-5-yloxy)ethyl]methylamino]propoxy]-5-methoxyphenyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one (Semotiadil), N-(1,1-dimethylethyl)-xcex1-methyl-xcex3-phenylbenzenepropanamine (Terodiline), xcex1-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)-benzeneacetonitrile (Verapamil);
(A4b):
2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridynedicarboxylic acid 3-ethyl 5-methyl ester (Amlodipine), 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-oxopropyl ester (Aranidipine), [S-(R.,R.)]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-pirrolidinyl ester (Barnidipine), (R.,R.)-xc2x1-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester (Benidipine) (E)-xc2x1-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxilic acid 2-methoxyethyl 3-phenyl-2-propenyl ester (Cilnidipine), 5-(5,5-dimethyl-1,3,2-dioxaphosphorinane-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylic acid 2-[phenyl(phenylmethyl)amino]ethyl ester P-oxide (Efonidipine), xc2x1-4-(1,3-benzodioxol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid 2-[[(4-fluorophenil)methyl]methylamino]ethyl1-methylethylester (Elgodipine), 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxilic acid ethyl methyl ester (Felodipine) 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid 5-methyl 3-(1-methyl)ethyl ester (Isradipine), (E)-4-[2-[3-(1,1-dimethylethoxy)-3-oxo-1-propenyl]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester (Lacidipine), 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedi-carboxilic acid 2-[(3,3-diphenyl-propyl)methylamino]-1,1-dimethylethyl methyl ester (Lercanidipine), 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxilic acid 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl methyl ester (Manidipine), 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2[methyl-(phenylmethyl)amino]ethyl ester (Nicardipine), 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester (Nifedipine), 2-cyano-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(1-methylethyl) ester (Nilvadipine), 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester (Nimodipine), 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methylpropyl ester (Nisoldipine), 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid ethyl methyl ester (Nitrendipine);
(A4c):
1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine (Cinnarizine), (E)-1-[bis(4-fluorophenyl)methyl]4-(3-phenyl-2-propenyl) piperazine (Flunarizine) 4-[4,4-bis (4-fluorophenyl)butyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (Lidoflazine), 1-[bis(4-fluorophenyl)methyl]-4-[(2,3,4-trimethoxyphenyl)methyl]piperazine (Lomerizine);
(A4d)
N,N-dimethyl-3-[[1-(phenylmethyl)-cycloheptyl]oxy]-1-propanamine (Bencyclane), 1-[2-[2-(diethylamino)ethoxy]phenyl]-3-phenyl-1-propanone (Etafenone), 3,4-dimethoxy-N-methyl-N-[3-[4-[[2-(1-methylethyl)-1-indolizinyl]sulphonyl]phenoxy]-propyl]benzeneethanamine (Fantofarone);
Class (A7):
the following groups of compounds belong to this class:
(A7a):
6-chloro-3,4-dihydro-3-[(2-propenylthio)methyl]-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Althiazide), 3,4-dihydro-3-(phenylmethyl)-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Bendroflumethiazide), (6-chloro-3-[[(phenylmethyl)thio]methyl]-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Benzthiazide), 6-chloro-3,4-dihydro-3-(phenylmethyl)-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Benzylhydrochlorothiazide), 6-chloro-3,4-dihydro-3-(2-methylpropyl)-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Buthiazide), 6-chloro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Chlorothiazide), 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl)benzebesulphonamide (Chlorthalidone), 6-chloro-3-(cyclopentylmethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Cyclopenthiazide), 3-bicyclo [2.2.1]-hept-5-en-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Cyclothiazide), 6-chloro-3,4-dihydro-3-[[(2,2,2-trifluoroethyl)tio]methyl]-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Epithiazide), 6-chloro-3-ethyl-3,4-di-hydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Ethiazide), 7-chloro-1,2,3,4-tetrahydro-4-oxo-2-phenyl-6-quinazolinesulphonamide (Fenquizone), 3-(aminosulphonyl)-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)benzamide (Indapamide), 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Hydrochlorothiazide), 3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Hydroflumethiazide), 6-chloro-3-(chloromethyl)-3,4-dihydro-2-methyl-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Methyclothiazide), 3,4-dihydro-6-methyl-2H-1-benzothiopyran-7-sulphfonamide 1,1-dioxide (Methycrane), 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulphonamide (Metolazone), 6-chloro-3-[(4-fluorophenyl)methyl]-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Paraflutizide) 6-chloro-3,4-dihydro-2-methyl-3-[(2,2,2-trifluoroethyl)thio]methyl]-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Polythiazide), 7-chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxo-6-quinazolinesulphonamide (Quinethazone), 6-chloro-3,4-dihydro-3-trichloromethyl-2H-1,2,4-benzothadiazine-7-sulphonamide 1,1-dioxide (Teclothiazide), 6-chloro-3-(dichloromethyl)-3,4-dihydro-2H-1,2,4-benzothadiazine-7-sulphfonamide 1,1-dioxide (Trichlormethiazide);
(A7b):
3,7-dihydro-1,3-dimethyl-7-(4-morpholinylmethyl)-1H-purine-2,6-dione (7-Morpholinomethyltheophylline), 3,7-dihydro-1-(2-hydroxypropyl)-3,7-dimethyl-1H-purine-2,6-dione (Protheobromine), 3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dione (Theobromine);
(A7c)
6-amino-3-ethyl-1-(2-propenyl)-2,4 (1H, 3H)-pyrimidinedione (Aminometradine), 6-amino-3-methyl-1-(2-methyl-2-propenyl)-2,4(1H,3H)-pyrimidinedione (Amisometradine);
(A7d):
N-phenyl-1,3,5-triazine-2,4-diamine (Amanozine), 3,5-diamino-N-(aminoiminomethyl)-6-chloropyrazinecarboxamide (Amiloride), N-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine (Chlorazanyl), [3-methyl-4-oxo-5-(1-piperidinyl)-2-thiazolidinylidene]acetic acid ethyl ester (Etozolin), 6-hydrazino-3-piridazinecarboxamide (Hydracarbazine), 5-amino-2[1-(3,4-dichlorophenyl)ethyl]-2,4-dihydro-3H-pyrazol-3-one (Muzolimine), 2-(2,2-dicylcohexylethyl)piperidine (Perhexiline), 6-phenyl-2,4,7-pteridinetriamine (Triamterene), 3-(aminosulphonyl)-5-(butylamino)-4-phenoxybenzoic acid (Bumetanide), 5-(amino sulphfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid (Furosemide), N-[[1-methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]-3-3-pyridinesulphonamide (Torasemide);
Class (A8): Apomorphine.
The preferred compounds in the (A1b) class are the following: when XA1=(IXa), RA1=CH2OH, RIA1=Cl, RIIIA1=RIVA1=free valences forming a xe2x80x94CHxe2x95x90CHxe2x80x94 double bond with the carbon atoms in 4 and 5 position of the heterocyclic ring of the formula (A1b), RIIA1=xe2x80x94(CH2)3xe2x80x94CH3, Losartan residue;
as in Losartan but with RA1=xe2x80x94O and RIIIA1 free valence, so as to form in combination with the carbon atom in 5 position of the heterocyclic ring of the formula (A1b) a ketonic group, RIA1 with RIVA1 and with the carbon atom in 4 position of the heterocyclic ring are such as to form the saturated ring having 5 carbon atoms (IXd), Irbesartan residue;
as in Losartan but with RIVA1=xe2x80x94Oxe2x80x94CH2xe2x80x94CH3, RA1 together with RIA1 and the carbon atoms in 4 and 5 position of the heterocyclic ring with RIVA1 and RIIIA1 free valences, are such as to form the aromatic radical containing a xe2x80x94COOH group (IXc), Candesartan residue;
as in Losartan but with XA1=xe2x80x94COOH, RA1=(IXb), RIA1=H, RIVA1 and RIIIA1 free valences form a double bond between the carbon atoms in 4 and 5 position in the heterocyclic ring of the formula (A1b), Eprosartan residue.
The preferred compounds of the A2 class are the following:
1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazol[4,3-d]-pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyll-4-methyl-piperazine (Sildenafil), 2-(2-propyloxyphenyl)-8-azapurin-6-one (Zaprinast).
The preferred compounds of the (A3) class are the following:
when RIB1=H, RIIB1 and RIIIB1=CH3, RVB1=H, RVIB1=RVIIB1=H,
m=n=1, XB1=xe2x80x94Oxe2x80x94, RIVB1=(XIp) wherein S1=S2=S4=H,
S3=xe2x80x94CH2xe2x80x94COxe2x80x94NH2, Atenolol residue;
as in Atenolol but with RIVB1=(XIs), Befunolol residue;
as in Atenolol, but with S3=S2=S4=H, S1=xe2x80x94CH2xe2x80x94CHxe2x95x90CH2, Alprenolol residue;
as in Atenolol, but with S1=COCH3, S3=xe2x80x94NHxe2x80x94COxe2x80x94(CH2)2xe2x80x94CH3, S2=S4=H, Acebutolol residue;
as in Atenolol, but with S3=xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94(cyclopropyl), Betaxolol residue;
as in Atenolol but with S3=xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH(CH3)2, Bisoprolol residue;
as in Alprenolol but with S1=(XIpII) and RIB1=CH3, Bufetolol residue;
as in Bufetolol, but with S1=xe2x80x94CN, Bunitrolol residue;
as in Bufetolol, but with S1=H, S4=Cl S2=CH3, Bupranolol residue;
as in Bufetolol but with S1=xe2x80x94COxe2x80x94(CH2)2xe2x80x94CH3, S3=F, Butofilolol residue;
as in Atenolol but with RIVB1=(XIpVIII), wherein B=xe2x80x94NHxe2x80x94, Carazolol residue;
as in Bufetolol, but with RIVB1=(XIpVII) wherein A=xe2x80x94CH2xe2x80x94CH2xe2x80x94, B=xe2x80x94NHxe2x80x94, W2=xe2x80x94O which with W1=free valence and the carbon atom in 1xe2x80x2 position forms a ketonic group, Carteolol residue;
as in Bufetolol but with S3=xe2x80x94NHxe2x80x94COxe2x80x94N(C2H5)2, S1=xe2x80x94COxe2x80x94CH3 Celiprolol residue;
as in Bufetolol but with S1=xe2x80x94Oxe2x80x94CH2xe2x80x94CONHxe2x80x94CH3, Cetamolol residue;
as in Bupranolol, but with S2=Cl Cloranolol residue;
as in Atenolol but with S3=xe2x80x94CH2xe2x80x94CH2xe2x80x94COOCH3, Esmolol residue;
as in Atenolol but with RIVB1=(Xiu) Indenolol residue;
as in Carteolol, but in RIVB1=(XIpVII) A=xe2x80x94CH2xe2x80x94, B=xe2x80x94COCH2xe2x80x94, W1=W2=H, Levobunolol residue;
as in Carteolol but with RIB1=H and in RIVB1=(XIpVII) A is a tertiary carbon atom and W1 free valence, so as to form a xe2x80x94CHxe2x95x90CHxe2x80x94 double bond between A and the carbon atom in 1xe2x80x2 position of (XIpVII), W2=CH3, Mepindolol residue;
as in Atenolol, but with S3=xe2x80x94(CH2)2xe2x80x94OCH3, Metoprolol residue;
as in Carteolol but in RIVB1=(XIpVII) A=xe2x80x94CH2xe2x80x94CH(OH)xe2x80x94, B=xe2x80x94CH2xe2x80x94, W2=OH, W1=H. Nadolol residue;
as in Atenolol but with S3=NO2, Nifenalol residue;
as in Mepindolol but in RIVB1=(XIpVII) A=xe2x80x94Oxe2x80x94CH2xe2x80x94, B=xe2x80x94CH2xe2x80x94, W2=xe2x80x94ONO2, W1=H, Nipradilol residue;
as in Alprenolol, but with S1=xe2x80x94Oxe2x80x94CH2xe2x80x94CHxe2x95x90CH2, Oxprenolol residue;
as in Bufetolol, but with S1=cyclopentyl, Penbutolol residue;
as in Mepindolol but with W2=H, Pindolol residue;
as in Atenolol but with S3=xe2x80x94NHxe2x80x94COCH3, Practolol residue;
as in Bufetolol but with S1=H, S3=xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(cyclohexyl), Talinolol residue;
as in Nipradilol but with RIB1=CH3, A=xe2x80x94Sxe2x80x94CH2xe2x80x94 and W2=H, Tertatolol residue;
as in Tertatolol but with RIVB1=(XIn), Tilisolol residue;
as in Bufetolol but with RIVB1=(XIo), Timolol residue;
as in Bufetolol but with S1=S2=CH3, Xibenolol residue;
as in Xibenolol but with RIB1=S1=H, Toliprolol residue;
as in Toliprolol, but with RIIB1=H and RIIIB1=(XIa), Bevantolol residue;
as in Carazolol but with RIIB1=H and RIIIB1=(XIb), Carvedilol residue;
when in the (A3) formula RIB1=RIIB1=RIIIB1=CH3, RVB1=(XIh), n=m=1, RVIB1=RVIIB1=H, XB1=xe2x80x94Oxe2x80x94, RIVB1=(XIg), Bopindolol residue;
as in Bufetolol but with RIVB1=(XIt), Bucumolol residue; when in the (A3) formula m=n=0 and RIVB1=(XIz) RIB1=RIIB1=RIIIB1=CH3, RVB1=H, Bufuralol residue;
as in Atenolol but with RIIIB1=(XIe) with YB1=H, n=m=0, RIVB1=(XIi) Butidrine residue;
as in Butidrine, but with RIIIB1=(XIe) with YB1=(XIf) with Z=H, RIVB1=(XIp) wherein S3=OH and S2=CONH2, S1=S4=H, Dilevalol residue;
as in Bevantolol but with S2=H, S1=CN, RIIIB1=(XIc), Epanolol residue;
as in Butidrine but with RIIIB1=CH3, RIVB1=(XIm), wherein the naphthalenic residue is linked by the carbon atom in 2 position to the carbon atom bringing the xe2x80x94ORIVB1 substituent, Pronethalol residue;
as in Pronethalol but with m=1 and XB1=xe2x80x94Oxe2x80x94, and RIVB1 is the naphthalenic residue (XIm) linked by the carbon atom in 1 position to XB1 Propranolol residue;
as in Pronethalol but with RIVB1=(XIp) with S1=S2=S4=H and S3=xe2x80x94NHxe2x80x94SO2xe2x80x94CH3, Sotalol residue;
as in Dilevalol but with S2=xe2x80x94SOCH3, and in para position to the other aromatic ring (form. XIf) z=xe2x80x94OCH3, Sulfinalol residue;
when in the (A3) formula RIB1=RIIB1=H, RIIIB1=(XId) with t =1, RVB1=H, n=m=0, RIVB1=(XId) with t=0, Nebivolol residue;
2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)amino]ethyl]benzamide (Labetalol), 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)carbonyl] piperazine (Terazosin), 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl) piperazine (Prazosin), benzonitrile,2-[2-hydroxy-3-([2-(1H-indol-3-yl)-1,1-dimethylethyl]amino]propoxy (Bucindolol).
In the (A4) class the preferred compounds are the following:
(A4a)
(2S-cis)-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4 (5H)-one (Diltiazem), xcex1-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methyl amino]propyl]-3,4-dimethoxy-xcex1-(1-methylethyl)benzeneacetonitrile (Verapamil);
(A4b):
2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester (Amlodipine), 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ethyl methyl ester (Felodipine) 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid 5-methyl 3-(1-methyl)ethyl ester (Isradipine) Lercanidipine, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2[methyl (phenylmethyl) amino]ethyl ester (Nicardipine), 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl (Nifedipine), 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylic acid 2-methoxyethyl 1-methylethyl ester (Nimodipine), 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl 2-methyl-propyl ester (Nisoldipine), 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylic acid ethyl methyl ester (Nitrendipine);
(A4c)
(E)-1-(bis(4-florophenyl)methyl]4-(3-phenyl-2-propenyl)piperazine (Flunarizine).
In class (A7) the preferred compounds are the following:
(A7a):
6-chloro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Chlorothiazide), 2-chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1-yl)benzebesulphonamide (Chlorthalidone), 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide (Hydrochlorothiazide), 3-(aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-1H-indol-1-yl)benzamide (Indapamide), 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulphonamide (Metolazone), 7-chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxo-6-quinazolinesulphonamide (Quinethazone);
(A7d):
3,5-diamino-N-(aminoiminomethyl)-6-chloropyrazinecarboxamide (Amiloride), 6-phenyl-2,4,7-pteridinetriamine (Triamterene), 3-(aminosulphonyl)-5-(butylamino)-4-phenoxybenzoic acid (Bumetanide), 5-(amino sulphonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid (Furosemide), N-[[(1-methylethyl)amino]carbonyl]-4-[(3-methylphenyl)amino]3-pyridinesulphonamide (Torasemide).
Particularly preferred compounds according to the present invention are the following:
The precursors of the salts belonging to the above mentioned classes are prepared according to the methods described in xe2x80x9cThe Merck Index 12a Ed.xe2x80x9d (1996), herein incorporated by reference. The Zaprinast preparation method is described in the DE patent 2,162,096. The Bucindolol preparation method is described in the G.B. patent 2,001,633.
In the compositions according to the present invention also the isomers of the compounds belonging to the above described classes can be used. Example of isomers are cis-, trans-, optical isomer D and L or the racemic, enantiomer. In general one isomeric form has higher activity with respect to the other, e.g., D form with respect to L form or vice versa.
The salts of the compounds belonging to these classes contain at least a nitrate ion mole/compound mole. Preferably the ratio between the nitrate ion moles and the precursor ones is unitary. Salts having higher molar ratio are obtained when in the molecule other aminic groups basic enough to be salified are present.
The salts of the present invention are formulated in the corresponding pharmaceutical compositions according to the well known techniques in the field, together with the usual excipients; see for example the xe2x80x9cRemington""s Pharmaceutical Sciences 15a Ed.xe2x80x9d volume.
The dose of the invention salts in their pharmaceutical compositions are the same, and generally lower than those of their precursors of the mentioned classes.
The salts of the present invention are obtainable according to one of the following methods:
When the substance to be salified is available as free base or as a corresponding salt soluble in an organic solvent, which preferably does not contain hydroxyl groups, for example acetonitrile, ethyl acetate, tetrahydrofuran, etc., the salt is prepared by dissolving the substance in the solvent at a concentration preferably equal to or higher than 10% w/v, adding the amount of concentrated nitric acid corresponding to the moles of salifiable aminic groups present in the compound. The nitric acid is preferably diluted in the same solvent. Preferably during and after the addition the mixture is cooled to temperatures in the range 20xc2x0 C.-0xc2x0 C. The product is generally recovered by filtration and washed with the solvent.
When on the contrary the substance is not very soluble, or it is available as a not very soluble salt in the above mentioned solvents, the corresponding mixtures with hydroxylated solvents can be used. Examples of such solvents are methyl alcohol, ethyl alcohol and water. Precipitation can be quickened by diluting then the so obtained mixture, after the addition of nitric acid, with an apolar solvent.
When the starting product is salified with hydrochloric acid, it is possible to prepare the salt with nitric acid directly adding silver nitrate to the compound solution. After filtering silver chloride, the solution is concentrated and cooled to recover the nitrate salt.
When the starting product is a salt, it is also possible to liberate the corresponding base by a treatment with a sodium or potassium bicarbonate or carbonate saturated solution, or with a sodium or potassium hydroxide diluted solution. The base is then extracted by a suitable organic solvent (for example halogenated solvents, esters, ethers), which is then dried. The organic solution is evaporated and then one proceeds according to the preceding preparation methods, by dissolving the base in acetonitrile or in the other above mentioned solvents.
The nitrate salts can be obtained also by using precursors of the described classes containing in the molecule a xe2x80x94ONO2 group bound by a linking bridge prepared as described in the European patent 759,899 in the name of the Applicant herein incorporated by reference.
The following examples are given only for illustrative purposes and they are not a limitation of the same.